Translational Chemical Biology: Hunt for Next Generation Chemical Probes/Drug Candidates in the Cancer Cell Signaling Arena.

Transcription

1 Translational Chemical Biology: unt for Next Generation Chemical Probes/Drug Candidates in the Cancer Cell Signaling Arena Prabhat Arya 1

2 small molecule binder From enzymes /isolated protein targets Rethinking Drug Discovery Pharma Focus Asia, Nov 2014 Well defined Compact Deep pocket Protein complexes/ signaling pathways 2

3 Map large surface area Shallow surface Combination of several weak interactions Extended hydrophobic interactions Possible hot spots May 14, 2014 Issue Theme: Chemical Biology of Protein-Protein Interactions 3

4 Natural Products as Modulators of PPIs Me Me Me Me N Me FK506 Me Me Me 2 N Eribulin Complex 3D architectures! Dense display of stereo-defined groups 4

5 Growing Faith in the Emerging Chemical Biology Model Modern rganic Synthesis Novel Chemical Toolbox Biologically Relevant Chemical Space Natural Product-like Natural Product-inspired ybrid Natural Products Cell Signaling Biology (Biological Questions/ Novel Assays) Cellular Assays Zebrafish Assays ther rganisms Biophysics and Structural Biology SPR Protein NMR Computational Tools 5

6 Exploring Biologically Relevant Chemical Space Bioactive Natural Products Building Macrocyclic Diversity-based Chemical Toolbox Natural Product- Inspired Substructures Natural product-like 3D architectures Sufficient complexity with a few chiral functional groups Incorporation of stereochemical and skeletal diversity Synthesis in a reasonable time-scale Easy to carry-out follow-up medicinal chemistry studies From Arya Research Team: Chem. & Biol. 145 (2002) and 163 (2005) Curr. pin. Chem. Biol. 247 (2005) Chem. Rev (2009)

7 Large 3D surface area Numerous binding interactions Excellent track record in finding bioactives Functionalized pre-organized dynamic Shapes Rich in chiral display of functional groups Nat. Rev. Drug Disc. 2008, 7,

8 Building A Chemical Toolbox Me Rapamycin N S Latrunculol A N Me Me 2 N Eribulin Epothilone/Ixabepilone 8

9 Latrunculins as Actin Modulators Isolated from Red Sea sponge Negombata magnifica Potent G-actin Inhibitors Latrunculol A is more potent compared to other family members J. Med. Chem. 2008, 51,

10 Latrunculin-derived ybrid Macrocycles Diversity site R 1 N R1 N Me Me PMBN PMBN Madhu Aeluri S S 10

11 Synthesis of ybrid Macrocycles TBDPS Me PMBN S i. Na, allyl bromide DMF,RT,5h ii.tbaf,tf,rt,1h 70%for2steps ~10.0 gms scale Me PMBN S R N EDCI, DMAP, DCM RT,4h,85-90% R N R N Me PMBN S i.g-ii(10mol%) DCM,reflux,3h ii. 2,10%Pd/C Et,RT,12h 60%for2steps Me PMBN S R=i-Pr R=Bn R=i-Bu R=s-Bu R=Me Aeluri, Dasari, Arya, rg. Lett ASAP 11

12 Eribulin as A Tubulin Binder FDA approved anticancer drug (Nov, 2010) marketed by Esai Synthetic analog of a marine sponge natural product, alichondrin B Mechanistically, a unique inhibitor of microtubule dynamics 12

13 ur 1 st Generation ybrid Macrocycles Eribulin Macrocycle N R Jimmidi, Krishna Reddy, Arya rg. Lett ASAP Ravi Kumar Jimmidi 13

14 ybrid Rapamycins Nat Rev Cancer 2006 Me N Me Me Nat Rev Neuroscience

15 ur 1 st Generation Plan Shiva Krishna Reddy Guduru Me N Me 16 Me Practical and scalable synthesis 22-membered macrocyclic ring Imbedded Amino alcohol moiety as the diversity site N 1 R 2 16 N 18 R 1 Krishna Reddy Guduru, Jimmidi, Deora, Arya rg. Lett ASAP 15

16 Collaborative Study: Probing Cancer Stem Cells by Small Molecules Dr. Satish Kitambi Dept of Medical Biochem and Biophysics, Karolinska Institutet Dr. Subhadra Dravida Tran-Scell Biologics yderabad Dr. Kiranam Chatti DRILS yderabad (Zebrafish / Cytoskeleton Signaling) Dr. Prasenjit Mitra DRILS yderabad (Mitochondria Signaling) 16

17 Nat. Rev. Drug Discovery July

18 Nat. Rev. Drug Discovery July

19 ur Collaborative Roadmap Isolation of Cancer Stem Cells (CSCs) from human brain tumor. Validation of Cancer Stem Cells. Identification of small molecules as highly selective killers of CSCs. Understanding of specific pathways affected by small molecule hits! Cell survival assays using CSCs vs cancer cells. Cell survival, proliferation and migration assays with CSCs in zebrafish. 19

20 Cell 2009 Salinomycin C 20

21 Cell 2014 Kitambi Karolinska 21

22 Cell Viability Assay (Cancer Stem Cells Derived from uman Brain Tumor Cells) Inte ensity (a. u) ATP measurement! Me Me N N N NMe from our toolbox Apoptosis inducer (by Caspase 3 activation) Compounds Kitambi Karolinska 22

23 Cancer Stem Cells: Proliferation and Cell Migration in Zebrafish Model! Lateral view of 2 days old zebrafish larvae with DAPI (stains all the nucleus as blue) and the newly transplanted CSC in red Dorsal view of approximately 1 month old zebrafish transplanted with CSCs labelled red brain brain eye Cancer Stem Cells Kitambi Karolinska 23

24 Sincere Thanks to Arya Academic Research Team in Canada (past) and India (2009- present) NRC Canada Genomics and ealth Initiative Science and Technology Park University of Pune Chemical Biology McGill University Chemical Biology Program Broad Institute of arvard and MIT